CREBBP
Overview
CREBBP (CREB-binding protein), also known as CBP, is a transcriptional coactivator that plays a crucial role in regulating gene expression. It is encoded by the CREBBP gene located on chromosome 16p13.3. CREBBP is involved in various cellular processes, including cell growth, differentiation, and apoptosis. It functions by interacting with numerous transcription factors and other proteins, thereby modulating their activity. Mutations or alterations in the CREBBP gene have been associated with several human diseases, including Rubinstein-Taybi syndrome and various cancers.
Structure and Function
CREBBP is a large protein consisting of 2,441 amino acids. It contains several functional domains, including a KIX domain, a bromodomain, a HAT (histone acetyltransferase) domain, and a Q-rich domain. Each of these domains contributes to the protein's ability to interact with other molecules and perform its functions.
The KIX domain is responsible for binding to transcription factors such as CREB (cAMP response element-binding protein) and MYB (myeloblastosis oncogene). The bromodomain recognizes and binds to acetylated lysine residues on histone tails, facilitating chromatin remodeling. The HAT domain acetylates histones and other proteins, leading to changes in chromatin structure and gene expression. The Q-rich domain is involved in protein-protein interactions.
Role in Gene Regulation
CREBBP acts as a coactivator for numerous transcription factors, enhancing their ability to activate gene expression. It does so by acetylating histones, which leads to a more open chromatin structure and increased accessibility of the DNA to the transcriptional machinery. Additionally, CREBBP can acetylate non-histone proteins, such as transcription factors, thereby modulating their activity.
One of the primary functions of CREBBP is to mediate the transcriptional response to cAMP signaling. When cAMP levels rise, CREB is phosphorylated and binds to CREBBP, which in turn acetylates histones and other proteins to activate the transcription of cAMP-responsive genes. This pathway is crucial for various physiological processes, including memory formation and immune response.
Clinical Significance
Mutations in the CREBBP gene can lead to several disorders. One of the most well-known conditions associated with CREBBP mutations is Rubinstein-Taybi syndrome, a developmental disorder characterized by intellectual disability, distinctive facial features, and broad thumbs and toes. This syndrome is caused by heterozygous mutations or deletions in the CREBBP gene, leading to haploinsufficiency.
CREBBP is also implicated in cancer. Somatic mutations and deletions of the CREBBP gene have been identified in various cancers, including acute myeloid leukemia (AML), non-Hodgkin lymphoma, and small cell lung cancer. These mutations often result in the loss of CREBBP's HAT activity, leading to dysregulation of gene expression and contributing to oncogenesis.
Therapeutic Implications
Given its role in gene regulation and disease, CREBBP is a potential target for therapeutic intervention. Inhibitors of the bromodomain and HAT domain of CREBBP are being explored as potential treatments for cancer and other diseases. For example, small molecule inhibitors that target the bromodomain of CREBBP have shown promise in preclinical studies for the treatment of leukemia and lymphoma.
Additionally, gene therapy approaches aimed at correcting CREBBP mutations or restoring its function are being investigated for the treatment of Rubinstein-Taybi syndrome and other genetic disorders. These strategies include the use of viral vectors to deliver functional copies of the CREBBP gene to affected cells.
Research Directions
Ongoing research is focused on understanding the detailed mechanisms by which CREBBP regulates gene expression and contributes to disease. Studies are exploring the interactions between CREBBP and various transcription factors, as well as the effects of CREBBP-mediated acetylation on chromatin structure and function.
Another area of interest is the development of novel therapeutic agents that target CREBBP. High-throughput screening methods are being used to identify small molecules that can modulate the activity of CREBBP or its interacting partners. These efforts aim to develop new treatments for cancers and genetic disorders associated with CREBBP dysfunction.